IACC Autism Spectrum Disorder Research Portfolio Analysis: Project Listing
Project Id Project Number Sub Project Number Funder Principal Investigator Project Title Project Description Fiscal Year Funding Category Strategic Plan Objective Objective Status Code Arra Funded? Federal/Private Institution State/Country Project Status Web Link 1 Web Link 2 Web Link 3 Active Current Award Period
Project Id: 3728 95252 None Simons Foundation Beaudet, Arthur Studies of postmortem brain searching for epigenetic defects causing autism Autism can arise from mutations that disrupt the activity of some genes, but the mutations discovered so far explain only a modest fraction of autism cases. Arthur Beaudet and his colleagues at Baylor College of Medicine are instead focusing on the epigenetic systems that control whether a gene is turned on or off through the regulation of genome structure.In the nucleus, DNA wraps around proteins to form a structure known as chromatin, and epigenetic modifications to either the proteins or the DNA can determine whether the chromatin hides or exposes a gene for RNA production. These modifications can include methylation of DNA at cytosine bases in the gene regulatory regions or adding methyl-, phosphate- or acetyl-groups to the wrapped histone proteins. Chromatin modifications can have a wide-ranging impact on which genes are expressed, even without a mutation in the DNA sequence.Beaudet and his colleagues are looking for unusual patterns of chromatin modifications associated with autism, using techniques that uncover these marks on the proteins and DNA recovered from the nuclei of neurons. From the postmortem brain tissue from people with autism, the team plans to isolate chromatin and use antibodies to detect particular histone modifications known to affect gene expression. The researchers will also sequence the isolated DNA, looking for both mutations and methylation marks; they have already used these techniques to detect known epigenetic abnormalities associated with Prader-Willi and Angelman syndromes, developmental disorders that present with learning disabilities and some autism-like symptoms.This combined strategy allows unbiased screening of the chromatin in the neuron nuclei across the entire genome but the researchers will also meticulously analyze autism-associated genomic regions with even higher resolution to detect any epigenetic changes that would not be detected by traditional sequencing. In a complementary set of experiments, the investigators are carefully assaying the neurons' RNA profiles to determine which genes are up- or down-regulated in autism, which may point to new genes or pathways.Epigenetic modifications can vary between tissues, so the researchers are starting with brain samples. But if the marks they discover are also found in other tissues, such as blood or skin, a simpler screen could perhaps be developed for earlier and more accurate diagnoses of autism. $400,000.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Private Baylor College of Medicine Texas Ongoing http://sfari.org/author/?author=https://id.sfari.org/arthurbeaudet No URL available. No URL available. active 2008-2011
Project Id: 3724 5M01RR000188-46 6534 National Institutes of Health Beaudet, Arthur The role of the Rett gene, chromosome 15q11-q13, other genes, and epigenetics Rare cases of genetic or epigenetic diseases can provide major insights into more common factors of the same or similar phenotypes. For example, a few genetic or epigenetic conditions can present with typical autism, including fragile X syndrome, tuberous sclerosis, mutations in the MECP2 gene (causing Rett syndrome), and mutations within chromosome 15q11-q13. There may be more patients diagnosed with autism spectrum disorders (ASD) that have mutations or epimutations involving MECP2, genes within chromosome 15q11-q13, and the loci causing fragile X syndrome and tuberous sclerosis than are currently recognized. Additionally, genes that interact with MECP2 and UBE3A are candidate genes for mutation or epimutation causing autism. This study will use in depth genotype/phenotype and epigenotype/phenotype correlations in autistic patients with known abnormalities in MECP2 and UBE3A genes and regions to provide insight into more common forms of autism. Mutation and epimutation analyses on other autism candidate genes will be performed based on their potential to explain the male predominance in autism or their relationship to the functional, biochemical, or regulatory pathways of the genes that cause disorders with phenotypes similar to ASD. $13,734.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Federal Baylor College of Medicine Texas Ongoing http://projectreporter.nih.gov/project_info_description.cfm?aid=8166670&icde=8965742 No URL available. No URL available. active 2009-2010
Project Id: 3723 2R01HD037283-11A2 None National Institutes of Health Beaudet, Arthur Human neurobehavioral phenotypes associates with the extended PWS/AS domain Genetic variation on chromosome 15 (e.g., 15q11-q13) is common and can cause numerous brain disorders, including Prader-Willi syndrome, Angelman syndrome, mental retardation, autism, epilepsy, schizophrenia, and bipolar disorder. Researchers in this study will better define genotype/phenotype correlations stemming from mutations and gene alterations in this region of chromosome 15. They will utilize gene expression analysis and epigenetic studies of human brain tissue comparing duplications of the 15q11-q13 region with controls. Duplications of this region on the maternal chromosome specifically cause autism, while duplications on the paternal chromosome do not. Therefore, understanding the molecular basis for this difference should shed considerable light on the causes of autism that are not caused by changes in DNA sequence. $634,739.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Federal Baylor College of Medicine Texas New http://projectreporter.nih.gov/project_info_description.cfm?aid=7985750&icde=8904715 No URL available. No URL available. active 2010-2015
Project Id: 3716 2230 None Autism Speaks Beaudet, Arthur DNA methylation and other epigenetic studies of autism brain This study is looking for abnormal gene expression patterns in the brains of individuals with autism. One way that genes are turned off is through DNA methylation: an enzyme places a methyl group onto certain sequences of DNA, thus flagging those genes for silencing. Thus, by examining the methylation status of genes, one can tell whether the gene is turned off or not. Researchers will examine the methylation patterns of genes taken from post-mortem brain tissue of autistic individuals and compare them to tissue from controls. The primary tool for analysis will be DNA microarrays ("gene chips"), which allow a genome-wide scan. $43,986.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Private Baylor College of Medicine Texas Ongoing http://www.autismspeaks.org/science/grants/dna-methylation-and-other-epigenetic-studies-autism-brain?destination=science%2Fgrant-search%2Fresults%2Fbeaudet No URL available. No URL available. active 2008-2010
Project Id: 3729 95349 None Simons Foundation Chess, Andrew Genome-wide analyses of DNA methylation in autism Small variations in the DNA sequence of a gene, called polymorphisms, are known to have an impact on normal and disease phenotypes. Some polymorphisms change the length or makeup of the resulting protein, whereas others interfere with binding sites for molecules that regulate the gene's expression.Andrew Chess and his colleagues at Massachusetts General Hospital are exploring a new way by which polymorphisms can control gene regulation - by influencing the addition of methyl groups to the DNA strand, impeding its expression. Most studies of DNA methylation have focused on discrete clusters at the beginning of genes, but Chess and colleagues are looking more broadly at methylation near polymorphisms throughout the genome. The researchers plan to explore whether and how a mechanism involving polymorphisms and methylation might be at work in autism.To analyze methylation across the genome, the researchers digest the entire genome using special enzymes that break the DNA strand at all potential methylation sites, except those that are actually methylated. The remaining DNA fragments can then be analyzed to determine which polymorphisms they represent. Chess and his team plan to use this technique to look for differences in methylation patterns between individuals with autism and healthy controls. They also plan to analyze identical twin pairs in which only one twin has autism in the hopes of uncovering a reason for the difference. The findings may lead to the discovery of genes that cause autism when their expression is altered by methylation.Researchers have already linked polymorphisms to methylation in DNA from unaffected individuals, with the interesting qualification that the variations specify only a greater propensity toward methylation and not necessarily constant methylation. This highlights the importance of analyzing methylation status, as looking at genetic sequence alone may not provide the complete picture on heritable DNA alterations. Another useful feature of the methylation sites they are examining is that the patterns are similar regardless of whether the genes are turned on or off, so their impact on autism can be studied using easily accessible cells such as blood cells rather than requiring brain samples. The researchers' new technique may supplement the usual genetic analyses in studying the complex heritability of autism. $400,000.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Private Massachusetts General Hospital Massachusetts Ongoing http://sfari.org/funding/grants/abstracts/genome-wide-analyses-of-dna-methylation-in-autism No URL available. No URL available. active 2008-2011
Project Id: 3733 4802 None Autism Speaks Rissman, Emile Epigenetics, hormones and sex differences in autism incidence Across studies, the ratio of males to females affected with autism is approximately 4:1. Basic research on sex differences in behavior has shown that differences in circulating levels of gonadal hormones during fetal and infant development are responsible for most sexual dimorphism in adults. For normal male development to occur, sex hormones like testosterone act through estrogen receptors, which in turn also activate other genes and proteins. The activation of certain genes through the estrogen receptor, then, may partially explain the sex difference. The body produces natural testosterone and estrogen but environmental chemicals may mimic these compounds and produce deleterious effects during development. This study will use estrogen receptor knockout mice to determine sex-differences on many autism-like behaviors in mice as well as to identify genes which are affected by bisphenol A (BPA) in order to identify the mechanism of action of this environmental chemical and whether it may be linked to autism. $85,000.00 Causes Question 3: Short-term Objective K Green dot: Objective has greater than or equal to the recommended funding. No Private University of Virginia Virginia Ongoing http://www.autismspeaks.org/science/grants/epigenetics-hormones-and-sex-differences-autism-incidence?destination=science%2Fgrant-search%2Fresults%2Frissman No URL available. No URL available. active 2008-2011
Project Id: 3735 5R01MH086711-02 None National Institutes of Health Rissman, Emilie Sex chromosomes, epigenetics, and neurobehavioral disease Given the large sex differences in the prevalence of several neurobehavioral diseases (for example, autism is found 4 times more often in boys than in girls), this study focuses on epigenetic modification of mechanisms that underlie sex differences in behavior. This study will evaluate whether the endocrine disrupting compound, bisphenol A (BPA), can modify sex differences in behavior and, if so, whether it acts on X-chromosome genes that may be linked to diseases. Genetically engineered mice, molecular, genetic ,and behavioral methods will be used to reveal epigenetic interactions between sex chromosome genes and BPA. Specifically, the effects of sex chromosomes and BPA on juvenile social behavior in mice will be assessed, and gene expression arrays of candidate genes affected by BPA exposure during neural development will be conducted. The effects of BPA on DNA methylation and histone modification will also be examined. The goal of this research is to find genes and processes that can help diagnose, treat, and prevent mental illnesses. $382,757.00 Causes Question 3: Short-term Objective K Green dot: Objective has greater than or equal to the recommended funding. No Federal University of Virginia Virginia Ongoing http://projectreporter.nih.gov/project_info_description.cfm?aid=7900841&icde=6669394 No URL available. No URL available. active 2009-2012
Project Id: 3727 5R01MH089606-02 None National Institutes of Health Warren, Stephen Epigenetic marks as peripheral biomarkers of autism Autism is a common disorder whose causes are poorly understood. Both genetic and environmental influences are thought to act together causing autism. Epigenetics is an area that bridges genetic and environmental factors and commonly is studied by examining dynamic methylation changes to the DNA. Prior research screened a total of 78 autistic boys and their fathers by this method in 807 genes and found 116 methylation changes that together can correctly identify nearly 80% of the affected boys from their fathers. In this study, these data will be confirmed in a much larger set of genes in 1,200 autistic boys and their families, including unaffected brothers. These data not only could provide new insight into the causes of autism but could also result in a screening test for autism. $949,623.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. Yes Federal Emory University Georgia Ongoing http://projectreporter.nih.gov/project_info_description.cfm?aid=7936792&icde=6639234 No URL available. No URL available. active 2009-2011
Project Id: 3722 AR080091 None Department of Defense Wlodarczyk, Bogdan Toxicant-induced autism and mitochondrial modulation of nuclear gene expression Autism has been associated with epigenetic changes: Tiny chemical tags in the regulatory regions of genes that affect how genes express themselves by turning them on or off. One gene often decreased in expression in the brain tissue of autistic individuals is MECP2, a gene that governs the expression of genes crucial to brain development. Exposure to environmental pollutants is also thought to play a role in autism. These two phenomena both involve a small cellular organ called mitochondria. The suspect environmental pollutants are toxic to mitochondria, which play a critical role in epigenetics: Pollution exposure can lower the amount of mitochondrial DNA (mtDNA) in a cell, causing an increase in placement of epigenetic tags by DNMT1 that leads to gene silencing. We hypothesize that exposure during pregnancy to pollutants toxic to mitochondria causes a decrease in mtDNA copy number and increased placement of epigenetic tags by DNMT1 on key developmental genes, affecting pathways that have direct roles in the development of autism. We will expose mice, during pregnancy, to selected toxicants and evaluate adult behavior and associated biochemical changes in brain tissue. Valproic acid will be used as a positive control, with saline as a negative control. The environmental pollutants lead, arsenic, cadmium, manganese, mercury, and permethrin will be investigated for their potential to induce autistic behavior changes. Brain tissue will then be used for molecular studies of mtDNA copy number, expression of DNMT1, and alterations to the epigenome on both a genomewide and gene-specific level. $0.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Federal Texas A&M University Texas Ongoing http://cdmrp.army.mil/search.aspx No URL available. No URL available. active 2009-2010
Project Id: 3725 1R01HD064743-01 None National Institutes of Health Chang, Qiang In vivo function of neuronal activity-induced MeCP2 phosphorylation MeCP2 (methyl-CpG binding protein 2) functions as a molecular linker between DNA methylation, chromatin remodeling, and transcription regulation. Mutations in the X-linked human MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder that predominantly affects females. To understand the molecular mechanism of RTT, it is important to study how MeCP2 dynamically regulates gene transcription and to reveal the physiological significance of such regulation. Recent biochemical analysis has identified 8 phosphorylation sites on the MeCP2 protein. Among these, serine 80 (S80) is phosphorylated in resting neurons but dephosphorylated in active neurons, whereas serine 421 (S421) is dephosphorylated in resting neurons but phosphorylated in active neurons. Differential phosphorylation of MeCP2 in response to neuronal activity may serve as a molecular switch in dynamically modulating neuronal gene expression, leading to important consequences in development and function of the adult brain. To test this hypothesis in vivo, several novel Mecp2 knock-in alleles carrying point mutations that either abolish or mimic phosphorylation at S80 and S421 on the MeCP2 protein have been generated. As a part of a long-term goal to understand the dynamic role of MeCP2 in DNA methylation-dependent epigenetic regulation of mammalian brain development and functions, this project will study the effects of manipulating MeCP2 phosphorylation on animal behavior, study the effects of manipulating MeCP2 phosphorylation on adult neurogenesis, and study how MeCP2 phosphorylation regulates its binding to the brain-derived neurotrophic factor (Bdnf) promoter, remodels chromatin and subsequently alters BDNF expression and neuronal activity. Together, these experiments will provide insights into the central role of neuronal activity-induced differential phosphorylation of MeCP2 in regulating neuronal gene expression and its functional significance in neuronal development and animal behavior. $304,917.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Federal University of Wisconsin - Madison Wisconsin New http://projectreporter.nih.gov/project_info_description.cfm?aid=7865394&icde=8914340 No URL available. No URL available. active 2010-2015
Project Id: 3726 5R01ES017646-02 None National Institutes of Health Fallin, Margaret; Feinberg, Andrew Environment, the perinatal epigenome, and risk for autism and related disorders This project will take a comprehensive genome-wide approach to understand the interplay between genetics, epigenetics, and in utero environment in birth and early development phenotypes that are important predictors of adverse outcomes generally, and are related to ASD specifically. $1,771,110.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Federal Johns Hopkins University Maryland Ongoing http://projectreporter.nih.gov/project_info_description.cfm?aid=7923297&icde=6639056 No URL available. No URL available. active 2009-2014
Project Id: 3719 AR080125 None Department of Defense Feinberg, Andrew Discordant monozygotic twins as a model for genetic-environmental interaction in autism While environmental factors likely play an important role in the development and evolution of autism, their specific mechanism and, most importantly, their gene targets are unknown. We intend to study mechanisms by which the environment influences autism by studies in the exciting new field of epigenetics that links genes, environment, and disease. Epigenetics is a form of hereditary information that does not involve DNA sequence (i.e., the genetic code), but it influences whether a gene is turned on (i.e., whether the code is read). A major component of epigenetics is DNA methylation, a chemical change in DNA that is reproduced during cell division and is associated with gene silencing. DNA methylation is affected by a variety of environmental factors including diet. We hypothesize that epigenetic abnormalities contribute to the etiology of autism, and that by studying these abnormalities we could better understand autism's clinical variability as well as identify genes that may undergo epigenetic change in some patients, and conventional mutations in the genetic code in others. A compelling argument in support of our hypothesis is that monozygotic (genetically identical) twins are often discordant for autism, i.e., there is marked disparity in the degree of autism, suggesting the importance of factors other than the DNA sequence, like DNA methylation. We will test this idea by studying DNA methylation in such monozygotic twins who are discordant for autism. As demonstrated in our preliminary findings, we have already discovered genes that are abnormally methylated in the more affected twin. We will then examine whether the identified epigenetic changes are relevant to most patients with autism, by determining whether the same genes show altered DNA in autistic subjects in the general population, compared to control individuals. We will also determine whether patients not showing altered DNA methylation in these genes have conventional DNA sequence changes in the same genes, potentially linking genetic and epigenetic alterations in autism. This project will combine novel and sensitive high-throughput epigenomics strategies developed by the Initiating Principal Investigator (PI), a pioneer in epigenetics, with detailed phenotypic analyses by the Partnering PI, a leader in the study of autism in genetic disorders. These studies should have immediate practical implications for autism diagnosis. In addition, this work raises the exciting possibility of discovering mechanisms for autism that might be treatable, since epigenetic changes are potentially reversible, unlike DNA sequence mutations. $0.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Federal Johns Hopkins University Maryland Ongoing http://cdmrp.army.mil/search.aspx No URL available. No URL available. active 2009-2012
Project Id: 3730 SFARI-07-17 None Simons Foundation Gingrich, Jay Identification of aberrantly methylated genes in autism: The role of advanced paternal age Autism arises from mutations in the genome, but several studies have shown that many of these mutations occur de novo — that is, they are non-inherited mutations introduced during the parents' gamete production. Jay Gingrich at the New York State Psychiatric Institute and his colleagues plan to study a mouse model of autism to investigate whether advanced paternal age is linked to a higher frequency of genomic aberrations.Sperm cells are generated throughout life without a clear decrease in viability or health, but recent surveys have found that children of older fathers have a higher risk of developing several disorders, including autism. Gingrich and colleagues have developed a model system in which to study the effects of aging on male fertility and sperm fitness. For four years, they have bred female mice with either young or old male mice to generate distinct mouse lines. In preliminary studies, mice with older fathers show several behavioral traits, such as a fear of unfamiliar mice and objects, that are often observed in people with autism. Gingrich proposes that these mice are a natural model for autism, and aims to study how paternal age affects the brain structure and behavior of their offspring.How aging alters sperm viability remains unclear. One possibility is that, over time, sperm stem cells acquire genomic aberrations such as mutations or an abnormal pattern of DNA modifications such as methylation. DNA methylation and other epigenetic modifications change the activity of genes without altering the genetic sequence. These patterns would be maintained in the genome and passed on during stem cell division. But the many divisions over years of sperm production could weaken the fidelity of this replication, and incorrect patterns could cause abnormal gene expression in the offspring.To examine this possibility, Gingrich and colleagues plan to use an unbiased, high-throughput method to study the methylation patterns in genomes isolated from the brain tissue of mice with young or old fathers. They hope to find specific regions in the genome that are more susceptible to age-related mis-methylation and to identify nearby genes that could be responsible for the abnormal behavior in the pups of older male mice. The researchers then plan to determine whether these loci are atypically methylated — and so misregulated — in people with autism. $374,835.28 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Private Research Foundation for Mental Hygiene, Inc. New York Ongoing http://sfari.org/funding/grants/abstracts/identification-of-aberrantly-methylated-genes-in-autism-the-role-of-advanced-paternal-age No URL available. No URL available. active 2007-2010
Project Id: 3717 4936 None Autism Speaks Jiang, Yong-Hui Maternal supplementation of folic acid and function of autism gene synaptic protein Shank3 in animal model The genetic basis of autism has been well established. In addition to changes in deoxyribonucleic acid (DNA) structure, other modifications, such as methylation or histone acetylation, may change gene expression in the absence of heritable mutations in DNA. Previous studies have indicated that environmental toxicants can influence gene expression through epigenetic mechanisms. Dr. Jiang has been working with a strain of mouse which have mutations in both SHANK 3 and Methylenetetrahydrofolate reductase (MTHFR), both implicated in autism spectrum disorder. He hypothesizes a link between folic acid and DNA methylation of SHANK3, producing abnormal gene expression. His lab will use this animal model to study whether administration of folic acid will increase 5-methylenetetrahydrofolate (5-MTHF) and cause DNA hypermethylation of synaptic proteins like SHANK3. Changes in the methylation status of these genes would not change the structure but may change the function of the gene such that differing levels of protein are produced, altering brain function and synaptic plasticity. Folic acid has been proven to reduce the incidence of major birth defects and is an important component of prenatal vitamins; however, this study will examine whether some mothers may be vulnerable to high doses of folic acid due to genetic variants of this pathway. $90,415.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Private Baylor College of Medicine Texas Ongoing http://www.autismspeaks.org/science/grants/maternal-supplementation-folic-acid-and-function-autism-gene-synaptic-protein-shank3-?destination=science%2Fgrant-search%2Fresults%2FJiang%2C+Yong-Hui No URL available. No URL available. active 2008-2010
Project Id: 3720 AR080125P1 None Department of Defense Kaufmann, Walter Discordant monozygotic twins as a model for genetic-environmental interaction in autism While environmental factors likely play an important role in the development and evolution of autism, their specific mechanism and, most importantly, their gene targets are unknown. We intend to study mechanisms by which the environment influences autism by studies in the exciting new field of epigenetics that links genes, environment, and disease. Epigenetics is a form of hereditary information that does not involve DNA sequence (i.e., the genetic code), but it influences whether a gene is turned on (i.e., whether the code is read). A major component of epigenetics is DNA methylation, a chemical change in DNA that is reproduced during cell division and is associated with gene silencing. DNA methylation is affected by a variety of environmental factors including diet. We hypothesize that epigenetic abnormalities contribute to the etiology of autism, and that by studying these abnormalities we could better understand autism's clinical variability as well as identify genes that may undergo epigenetic change in some patients, and conventional mutations in the genetic code in others. A compelling argument in support of our hypothesis is that monozygotic (genetically identical) twins are often discordant for autism, i.e., there is marked disparity in the degree of autism, suggesting the importance of factors other than the DNA sequence, like DNA methylation. We will test this idea by studying DNA methylation in such monozygotic twins who are discordant for autism. As demonstrated in our preliminary findings, we have already discovered genes that are abnormally methylated in the more affected twin. We will then examine whether the identified epigenetic changes are relevant to most patients with autism, by determining whether the same genes show altered DNA in autistic subjects in the general population, compared to control individuals. We will also determine whether patients not showing altered DNA methylation in these genes have conventional DNA sequence changes in the same genes, potentially linking genetic and epigenetic alterations in autism. This project will combine novel and sensitive high-throughput epigenomics strategies developed by the Initiating Principal Investigator (PI), a pioneer in epigenetics, with detailed phenotypic analyses by the Partnering PI, a leader in the study of autism in genetic disorders. These studies should have immediate practical implications for autism diagnosis. In addition, this work raises the exciting possibility of discovering mechanisms for autism that might be treatable, since epigenetic changes are potentially reversible, unlike DNA sequence mutations. $0.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Federal Kennedy Krieger Institute Maryland Ongoing http://cdmrp.army.mil/search.aspx No URL available. No URL available. active 2009-2012
Project Id: 3721 AR080117 None Department of Defense Millonig, James Epigenetic regulation of the autism susceptibility gene, ENGRAILED 2 (EN2) Risk to Autism Spectrum Disorder is likely a combination of genetic susceptibility and nongenetic environmental factors. Previous human genetic analysis has identified the ENGRAILED 2 (EN2) gene, an important regulator of CNS development, as a likely susceptibility locus. These studies demonstrated that certain EN2 genetic variants are inherited more often in individuals with ASD than unaffected siblings. Moreover, recent molecular analysis has demonstrated that these genetic variants are functional, increasing gene expression levels. EN2 levels are also increased in post-mortem samples from individuals with autism compared to unaffected controls.Environmental factors can influence gene expression levels. These factors can regulate expression through the differential methylation of cytosine nucleotides in DNA regions called CpG islands. Interestingly, numerous CpG islands are present in the EN2 gene, suggesting that their differential methylation may affect EN2 levels.To investigate this hypothesis, human neuronal cell lines that express EN2 will be treated with methyl donors and demethylating agents. The effect on DNA methylation and EN2 levels will then be quantified. In addition, methylation of the EN2 CpG islands will be quantified in the post-mortem samples and correlated with EN2 gene expression levels.If our hypothesis is correct that EN2 levels are regulated by differential methylation, future experiments will focus on identifying environmental agents that could affect methylation and expression levels. Our long-term goal is to better define the molecular pathways disrupted in ASD so that environmental risk factors and possible therapeutic targets can be identified. $0.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Federal University of Medicine & Dentistry of New Jersey - Robert Wood Johnson Medical School New Jersey Ongoing http://cdmrp.army.mil/search.aspx No URL available. No URL available. active 2009-2010
Project Id: 3718 4743 None Autism Speaks Plomin, Robert Identical twins discordant for autism: Epigenetic (DNA methylation) biomarkers of non-shared environmental influences The fact that some pairs of identical twins differ in autistic symptoms makes clear that there must be an important non-genetic (i.e., environmental) component as well that can differ even within a family (called non-shared environment). This project will investigate a major biological mechanism that can retain a long-lasting impression of the environment and which regulates gene expression: DNA methylation. Dr. Plomin's lab will study DNA methylation in a twin cohort called the "twins early development study" using a new technology to study the whole genome. First, this lab will examine differences in DNA methylation across identical twins discordant for autism. These differences can be caused by a "non-shared" environment within a family. In addition, they will study whether these differences are seen between those affected with autism and unrelated cases who are not diagnosed. Finally, the Plomin lab will examine epigenetic markers that differ in individuals who show a social vs. non-social phenotype. The proposed biological index of non-shared environmental influence will be a vital starting point for mapping out the environmental causal pathways that lead to autism spectrum disorder (ASD), which have special value because risky environments could be prevented or reversed more easily than risky genotypes. $89,030.00 Causes Question 3: Short-term Objective J Green dot: Objective has greater than or equal to the recommended funding. No Private King's College London United Kingdom Ongoing http://www.autismspeaks.org/science/grants/identical-twins-discordant-autism-epigenetic-dna-methylation-biomarkers-non-shared-en?destination=science%2Fgrant-search%2Fresults%2Fplomin No URL available. No URL available. active 2008-2011
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